Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
  • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
  • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
  • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
  • C07C275/66—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to halogen atoms or to nitro or nitroso groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
  • C07C335/30—Isothioureas
  • C07C335/36—Isothioureas having sulfur atoms of isothiourea groups bound to carbon atoms of six-membered aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D277/18—Nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D277/38—Nitrogen atoms
  • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
  • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
  • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
  • C07D317/66—Nitrogen atoms not forming part of a nitro radical

Definitions

• R 1 denotes C 1 -C 8 -alkyl, cycloalkyl having 3 to 8 C atoms or alkenyl having 3 to 4 C atoms
• R 2 , R 3 and R 4 are identical or different and denote hydrogen, halogen, alkyl or alkoxy each having 1 to 4 C atoms, methylenedioxy, ethylenedioxy, dimethyl-or diethylamino or trifluoromethyl
• R 5 denotes hydrogen or alkyl having 1 to 3 C atoms
• R 6 denotes hydrogen, or alkyl having 1 to 6 C atoms
• R 7 denotes hydrogen, alkyl having 1 to 12 C atoms, cycloalkyl having 3 to 12 C atoms, allyl, phenylethyl
• the invention further relates to a process for the preparation of the compounds of the general formula I, which comprises
• Inorganic acids H--A which can be used are, for example: hydrogen halide acids, such as hydrochloric acid and hydrobromic acid, and also sulfuric acid, phosphoric acid and amidosulfonic acid.
• Organic acids H--A which may be mentioned are, for example, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.
• the compounds of the formulae IV and XI are novel.
• the invention therefore further relates to compounds of the formula IV ##STR16## in which R 1 to R 5 and Y are as defined under formula I, and the acid addition salts thereof. These are suitable as precursors for the preparation of compounds of the general formula I.
• the invention also relates to compounds of the general formula XI ##STR17## in which R 1 to R 5 and Y are as defined under formula I and Z represents halogen, and the acid addition salts thereof, which can be used as intermediates in the preparation of compounds of the general formula I in accordance with procedure (a).
• the procedure designated under (a) is advantageously carried out by reacting the compounds II with the thioureas III in a molar ratio of 1:1 to 1:15. In general, no significant advantages are achieved by the use of larger molar excesses of thiourea.
• the reaction is advantageously carried out in inert polar organic solvents, such as dimethylformamide, dimethylacetamide, ethylene glycol monomethyl ether or ethylene glycol dimethyl ether, and particularly advantageously is carried out in strongly polar protic solvents, such as methanol, ethanol, isopropanol, n-butanol, acetic acid, propionic acid or formic acid, or in mixtures of the said solvents with water; anhydrous mixtures of the said solvents are also suitable.
• the reaction can also be carried out without the use of a solvent, by warming the reaction mixture to a temperature range between 80° and 220° C., preferably between 100° and 180° C. When a solvent is used, the reaction is carried out in a preferred temperature range of 60° to 150° C.
• reaction time is to a large extent dependent on the solvent and on the reaction temperature employed and in general is between 15 minutes and 24 hours.
• the quantitative course of reaction to give the compounds I according to the invention is advantageously followed by thin layer chromatography on silica gel plates.
• the compounds I according to the invention separate out in the course of the reaction in the form of their acid addition salts, which are sparingly soluble and can be filtered off; if this is not the case, the solvent is evaporated and, if appropriate, the yield can be increased by the subsequent addition of a suitable precipitating agent, such as, for example, ethyl acetate, diethyl ether, diisopropyl ether, acetone or acetonitrile.
• a suitable precipitating agent such as, for example, ethyl acetate, diethyl ether, diisopropyl ether, acetone or acetonitrile.
• Z in the general formula II denotes halogen, preferably chlorine
• the resulting compounds of the formula XI are reacted with ammonia or an amine HNR 6 R 7 to give the compounds I.
• Either aqueous solutions of ammonia and of the amines or liquid ammonia or the pure amines in excess can be used for this reaction, the excess ammonia or amine at the same time acting as the solvent.
• the reaction can also be carried out in organic solvents, such as, for example, dimethylformamide, dimethylacetamide, dimethylsulfoxide, dioxan, tetrahydrofuran or diethylene glycol dimethyl ether; particularly suitable solvents are, however, lower alcohols having 1 to 4 C atoms, such as, for example, methanol, ethanol or isopropanol.
• organic solvents such as, for example, dimethylformamide, dimethylacetamide, dimethylsulfoxide, dioxan, tetrahydrofuran or diethylene glycol dimethyl ether
• suitable solvents are, however, lower alcohols having 1 to 4 C atoms, such as, for example, methanol, ethanol or isopropanol.
• one mole of ammonia or amine in the presence of two moles of an auxiliary base are required for the conversion of the sulfonyl chlorides XI to the sulfonamides I.
• the procedure followed for the reaction can be to use at least 3 moles of ammonia or amine per mole of sulfonyl chloride XI.
• the use of 3-7 moles of ammonia or amine per mole of sulfonyl chloride is advantageous, but it is possible to use an even larger excess of amine.
• Suitable auxiliary bases are inorganic and organic hydroxides, carbonates and bicarbonates, and also salt solutions of weak inorganic and organic acids, and in all cases tertiary amines, such as, for example, triethylamine, tri-n-butylamine, methyl-dicyclohexylamine or ethyldicyclohexylamine, are particularly advantageous. If used in excess, the tertiary amine can likewise serve as the reaction medium, without the addition of a further solvent.
• the reaction proceeds exothermically, so that, advantageously, the reaction mixture is cooled and the reaction is carried out at temperatures between -35° and +100° C., preferably between +10° and +60° C.
• the reaction time should be at least 30 minutes and the reaction can be discontinued at the latest after two days, no significant advantages being achieved with longer reaction times.
• a reaction time of between 6 and 20 hours is preferred.
• the procedure employed for working up is, advantageously, to dilute with water, after distilling off the amine and concentrating the reaction mixture if necessary, whereupon the compounds I precipitate, as sparingly soluble compounds.
• R 6 or R 7 in the compound I prepared in this way denotes a hydrogen atom
• the pH should, as far as possible be adjusted to 7.5 to 8.5.
• the compounds of the formula XI can be obtained from compounds of the formula XII, or salts thereof, ##STR18## in which R 1 to R 5 , X, Y and Z are as defined under formula XI, by the elimination of water.
• This reaction is carried out under the conditions given under procedure (b), and is preferably carried out in glacial acetic acid or in solvents which distil as an azeotrope with water, such as methylene chloride, chloroform, dichloroethane, chlorobenzene, nitrobenzene, nitromethane, toluene or xylene, and, appropriately, the water formed during the reaction is determined by analysis.
• the reaction is carried out in the boiling solvents.
• the compounds XI are obtained by heating the dry compounds XII to temperatures of 100° to 250° C. and preferably of 150° to 220° C.
• the water of condensation, which interferes, is removed by distilling off rapidly, preferably in a stream of air, or by applying an effective vacuum and using a desiccant.
• the compounds of the formula XI, and their salts can also be obtained from aniline derivatives XIII ##STR19## in a manner which is in itself known, by diazotizing and subsequently carrying out a Meerwein reaction.
• the compounds XIII can be prepared from aminoketones XIV, or their acid addition salts ##STR20## in which Y and R 5 are as defined and V represents H, by halogenation, preferably with elementary bromine or chlorine, and subsequent reaction of the halogenoketones XIV, in which V denotes Cl or Br, with a thiourea of the formula III under the conditions for carrying out procedure (a).
• thioureas III which are used are substances which have been described in the literature. They are prepared in a known manner, by reacting amines with isothiocyanates, carbon disulfide or thiophosgene (compare Houben-Weyl, "Methoden der organischen Chemie” ("Methods of Organic Chemistry"), Volume 9, page 384, 4th edition, Georg-Thieme-Verlag, Stuttgart, 1955).
• the compounds of the general formula II can be obtained by several methods described in the literature (compare, for example, German Offenlegungsschrift No. 2,436,263).
• polar organic solvents suitable solvents being protic solvents, such as lower alcohols having 1 to 6 C atoms, for example methanol, ethanol, propanol, iso-propanol or 1- or 2-butanol, ethylene glycol monomethyl ether, diethylene glycol monomethyl ether or lower aliphatic carboxylic acids, such as acetic acid, propionic acid or formic acid, or mixtures of the said solvents.
• protic solvents such as lower alcohols having 1 to 6 C atoms, for example methanol, ethanol, propanol, iso-propanol or 1- or 2-butanol, ethylene glycol monomethyl ether, diethylene glycol monomethyl ether or lower aliphatic carboxylic acids, such as acetic acid, propionic acid or formic acid, or mixtures of the said solvents.
• protic solvents such as lower alcohols having 1 to 6 C atoms, for example methanol, ethanol, propanol, iso-propano
• Catalysts which can be used are inorganic or organic proton acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, one of the aliphatic carboxylic acids mentioned as a solvent, or an aromatic carboxylic acid, such as salicylic acid or benzoic acid.
• the dehydration of the compounds IV can also be carried out without the use of a catalyst and also without the use of a solvent.
• the reaction is carried out in a temperature range between 0° and 200° C., lower temperatures resulting in long reaction times, and the danger of by-products being formed increasing at higher temperatures.
• the reaction is carried out at between 50° and 150° C., and particularly advantageously the reaction is carried out in boiling methanol, ethanol, propanol or glacial acetic acid.
• the quantitative course of the reaction is appropriately followed by recording the thin layer chromatogram on silica gel plates.
• reaction mixture is worked up by a procedure analogous to that indicated under procedure (a).
• the compounds of the general formula IV are obtained by methods which are in themselves known, for example by procedures analogous to those indicated in German Offenlegungsschrift No. 2,436,263. Reaction conditions which are as mild as possible and reaction temperatures and working-up conditions below 40° C. should be chosen if it is desired to prepare compounds of the formula IV which are as pure as possible.
• compounds of the general formula V are reacted with compounds of the formula VI, advantageously in a polar organic solvent, such as, for example, in lower alcohols having 1 to 4 C atoms, ethylene glycol monomethyl ether or ethylene glycol dimethyl ether, diethylene glycol monomethyl ether or diethylene glycol dimethyl ether, acetone, ethyl acetate or dimethylformamide.
• the reaction is advantageously carried out at between 0° and 80° C., preferably between 15° and 40° C., and, after the exothermic reaction has subsided, the reaction mixture is heated to temperatures between 60° and 140° C. in order to bring the formation of the compounds of the formula I to completion.
• the course of the reaction is appropriately followed by thin layer chromatography on silica gel plates.
• the reaction time is between 5 and 60 hours.
• Compounds V which prove particularly suitable for this reaction are, in particular, those which carry, on the sulfamoyl group, a bulky organic radical R 7 , such as, for example, tert.-butyl, as well as hydrogen as R 6 , or those compounds V in which R 6 and R 7 carry an organic radical as a substituent.
• the mercaptoketones of the formula V are reacted in an anhydrous, polar, inert solvent, such as, for example, in methyl acetate, ethyl acetate, dioxan or tetrahydrofuran, with the carbodiimides of the general formula VII in a molar ratio of 1:1.
• the reaction is carried out in a temperature range between 0° and 40° C., preferably between 10° and 30° C. After the weakly exothermic reaction has subsided, the reaction mixture is stirred for about 10-20 hours at 20° to 40° C.
• a protic solvent preferably methanol, ethanol, propanol, isopropanol, n-butanol, glacial acetic acid or water, or also mixtures of the said solvents
• the reaction mixture is heated at temperatures between 60° and 140° C. for a further 2 to 70 hours.
• the course of the reaction is appropriately followed by thin layer chromatography on silica gel plates.
• the compounds of the formula V which are used in procedures (c) and (d) can be prepared by methods known from the literature (for example German Offenlegungsschrift No. 2,436,263).
• the preparation of compounds of the general formulae VI and VII is also described in the literature (for example Chem. Ber. 97, 1232 (1964), Bull.Chem.Soc.Jap. 46, 1765 (1973), Angew.Chem. 74, 214 (1962) and Bull.Soc.Chim. Jap. 38, 1806 (1965)).
• the compounds of the general formula VIII are converted to the compounds of the formula I using a suitable oxidizing agent, preferably using active manganese-IV oxide.
• a suitable oxidizing agent preferably using active manganese-IV oxide.
• the solvents used are preferably halogenated hydrocarbons, such as, for example, methylene chloride, chloroform or tetrachloroethane, but particularly preferentially acetonitrile or mixtures of the said solvents with acetonitrile.
• the reaction is carried out in a temperature range between 0° and 40° C., preferably between 20° and 30° C., over a period of 10 to 60 hours, the oxidizing agent is then filtered off and, in order to bring the reaction to completion, the reaction mixture is heated, after adding an equal volume of a protic solvent such as methanol, ethanol, propanol, isopropanol, butanol or glacial acetic acid, for 1 to 30 hours at temperatures between 60° and 140° C.
• a protic solvent such as methanol, ethanol, propanol, isopropanol, butanol or glacial acetic acid
• the hydrolysis mixture can be warmed to temperatures of 40°-100° C., preferably of 60°-80° C., whilst monitoring the progress of the reaction by thin layer chromatography.
• the product mixture which has not yet been completely converted into the compounds I is worked up by filtration or extraction with a suitable solvent, such as methyl acetate, ethyl acetate or nitromethane, and is then treated in accordance with procedure (b).
• the compounds of the formula I can be reversibly reacted in a suitable solvent with an acid of the formula H--A.
• the compounds I can be introduced into the pure acids, preferably at temperatures between 0° and 60° C., if these are liquid or have a melting point not substantially higher than 60° C. and if they do not give rise to any side reactions.
• the reaction is carried out in a solvent, such as, for example, in water or in an organic solvent, such as, for example, in dioxan, tetrahydrofuran, ether, a lower alkyl acetate having 1 to 4 C atoms in the alkyl part, acetonitrile, nitromethane, acetone, methyl ethyl ketone or the like; lower alcohols having 1 to 4 C atoms and carboxylic acids having 2 to 4 C atoms have proved particularly suitable.
• 1-1.5 moles of the acids H--A are used per mole of the compounds I, but it is also possible to use larger amounts of acid.
• the reaction is carried out at temperatures between 0° and 120° C. and preferably between 10° and 60° C. The reaction is moderately exothermic.
• the compounds I When the reaction is carried out in aqueous solution, the compounds I in general dissolve immediately on addition of the acids H--A and only in rare cases do the corresponding acid addition compounds precipitate out.
• the salts according to the invention are appropriately isolated by evaporating off the water under mild conditions, preferably by freezedrying.
• the acid addition salts frequently precipitate as sparingly soluble compounds on the addition of the particular acid H--A. If a solution is obtained, the acid addition compounds are precipitated using a suitable precipitating agent, after prior concentration of the solution if necessary. Suitable precipitating agents are the solvents described for the same purpose in process (a).
• the acid addition products are very frequently obtained in the form of viscous oils or amorphous glassy products, even in a very high degree of purity. These amorphous products can frequently be made to crystallize by treatment with an organic solvent, by warming to 40° to 80° C. if necessary.
• Suitable crystallization-promoting solvents are, in particular, lower alkyl acetates having 1 to 4 C atoms in the alkyl part, such as methyl acetate, ethyl acetate and n-butyl acetate, and also lower dialkyl ketones, such as acetone or methyl ethyl ketone, lower dialkyl ethers, such as diethyl ether, diisopropyl ether or di-n-butyl ether, and also acetonitrile and nitromethane, and in some cases also lower alcohols, such as methanol, ethanol, isopropanol or n-butanol.
• lower alkyl acetates having 1 to 4 C atoms in the alkyl part such as methyl acetate, ethyl acetate and n-butyl acetate
• lower dialkyl ketones such as acetone or methyl ethyl ketone
• the acid addition products can be deprotonated in a suitable solvent by treatment with bases, to give the compounds of the general formula I.
• bases which can be used are solutions of inorganic hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide or barium hydroxide, carbonates or bicarbonates, such as sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate, ammonia and amines, such as triethylamine, dicyclohexylamine, piperidine and methyldicyclohexylamine.
• the free basic compounds I precipitate as sparingly soluble compounds and can be separated off and isolated by filtration or extraction with an organic solvent, preferably with ethyl acetate.
• Suitable organic reaction media are, in particular, lower alcohols having 1 to 4 C atoms, preferably methanol and ethanol, but it is also possible to use ethyl acetate, diethyl ether, tetrahydrofuran, dioxan, diethylene glycol dimethyl ether, dimethylformamide and others.
• the reaction to give the compounds I takes place spontaneously.
• the reaction is carried out at between -35° and 100° C., preferably between 0° and 60° C.
• the free bases of the formula I are precipitated, after prior concentration of the reaction mixture if necessary, by adding water. If a water-immiscible solvent is used, the procedure employed is, advantageously, to wash the reaction mixture, after the reaction has taken place, with water and to evaporate off the organic solvent, optionally after prior drying.
• Bases which can be used are hydroxides of the alkali metals and alkaline earth metals, preferably NaOH and KOH, alkali metal alcoholates and alkaline earth metal alcoholates, such as NaOCH 3 and NaOC 2 H 5 , NaH, sodium methylsulfinylmethide and the like.
• the solvents used are water or polar organic solvents, such as methanol, ethanol, isopropanol, n-butanol, dimethylformamide, dimethylsulfoxide, diethylene glycol dimethyl ether or acetonitrile.
• This reversible acid/base reaction can be used for purification of the compounds I.
• the salts XVII can be used in order to prepare compounds of the formula I which are correspondingly converted at the sulfonamide group by means of alkylation reactions.
• Water can be used as the solvent for alkylation reactions.
• these reactions are preferably carried out in the polar organic solvents mentioned and particularly advantageously are carried out in a two-phase mixture of water and a water-immiscible organic phase, such as, for example, toluene, benzene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl acetate or a mixture of the said solvents.
• phase transfer catalyst such as, for example, tetra-n-butyl-ammonium chloride, benzyl-triethyl-ammonium chloride, benzyl-dimethyl-tetradecylammonium chloride, tetra-n-butylphosphonium chloride or dicyclohexyl-[18]crown-6, can also be advantageous.
• the reaction is carried out in a temperature range of -20° to +100° C., preferably between +10° and 40° C., and the course of the reaction is followed by thin layer chromatography.
• R--X Conventional alkylating agents of the general formula R--X are used, in which R has the meaning of R 6 or R 7 and X represents, for example, bromine, chlorine, iodine, --O--SO 2 --OR, --O--SO 2 CH 3 or ##STR24##
• the salts XVII are advantageously produced without subsequent isolation in the indicated manner in the reaction mixture, by the action of one of the bases mentioned on the compounds I and subsequent or parallel addition of one of the alkylating agents R--X designated.
• Preferred compounds according to the invention are those of the general formula I in which the substituents have the meanings described below in Table 1:
• R 1 methyl, ethyl or cyclopropyl
• R 2 hydrogen, methyl, ethyl, bromine, chlorine, fluorine, trifluoromethyl, methoxy, ethoxy, --N(CH 3 ) 2 or --N(C 2 H 5 ) 2
• R 3 hydrogen, methyl, ethyl or chlorine
• R 4 hydrogen or methyl
• R 6 and R 7 hydrogen, methyl or ethyl, R 6 and R 7 being identical or different
• Y bromine, chlorine or methyl in the 2-, 3-or 4-position relative to the thiazole ring
• the compounds, according to the invention, of the formula I are valuable medicaments and are distinguished by a very advantageous effect on the serum lipoproteins. They can therefore be used as medicaments, especially for influencing the serum lipoproteins.
• the invention therefore also relates to pharmaceutical preparations based on the compounds of the formula I and their pharmacologically acceptable salts, and to the use as medicaments.
• hyperlipoproteinaemia constitutes a considerable risk factor for the development of arteriosclerotic vascular changes, especially in coronary heart disease.
• the lowering of elevated serum lipoprotein levels is therefore of exceptional importance for the prophylaxis and the regression of arteriosclerotic changes.
• it is very specific categories of serum lipoproteins which are concerned here, since the low density lipoproteins (LDL) and very low density lipoproteins (VLDL) constitute an atherogenic risk factor, whilst the high density lipoproteins (HDL) constitute a protective function against coronary heart disease.
• LDL low density lipoproteins
• VLDL very low density lipoproteins
• HDL high density lipoproteins
• hypolipidaemic agents should lower the levels of VLDL-cholesterol and LDL-cholesterol in the serum, but as far as possible should have no effect on, or should even increase, the HDL-cholesterol concentration.
• the compounds, according to the invention, which are mentioned here have valuable therapeutic properties. Thus, they lower, in particular, the concentration of LDL and VLDL, whilst the HDL fraction is either reduced to a substantially lesser extent or is even increased. They therefore represent a considerable advance, compared with the comparison compound clofibrate, as can be seen from the test described below. They can therefore be used for the prophylaxis and regression of arteriosclerotic changes, in that they eliminate a causal risk factor.
• This risk factor includes not only primary hyperlipoproteinaemia, but also certain secondary hyperlipidaemias, such as arise, for example, in diabetes.
• the relative liver weight is not changed by the compounds I, whilst clofibrate, which is used as a hypolipidaemic standard, results in a substantial increase in the relative liver weight.
• the cholesterol content of the lipoprotein fractions isolated in the ultracentrifuge was determined completely enzymatically by the CHOD-PAP method by means of the Boehringer-Mannheim test combination and the values obtained were converted to ⁇ g/ml of serum.
• the change in the lipoprotein cholesterol in the treated group compared with that in a control group included in the study under the same conditions is shown in the table given.
• clofibrate effects an approximately equal lowering of the LDL fraction and a severe lowering of the HDL fraction, whilst the novel compounds exert a powerful selectively lowering action on the atherogenic lipoprotein fractions (VLDL and LDL) and leave the protecting HDL fraction essentially unaffected, or even increase this fraction.
• a therapeutic formulation of the compounds of the formula I can be, in particular, in the form of tablets, sugar-coated tablets, capsules, suppositories or syrups.
• the novel compounds can be used either on their own or as a mixture with pharmacologically acceptable excipients.
• An oral administration form is preferred.
• the active compounds are preferably mixed with substances which are in themselves known and converted, by methods which are in themselves known, to suitable administration forms, such as tablets, gelatin capsules, aqueous or oily suspensions or aqueous or oily solutions.
• Inert excipients which can be used are, for example, magnesium carbonate, lactose or maize starch, with the addition of other substances, such as, for example, magnesium stearate.
• the formulation can be prepared in the form of either dry granules or moist granules.
• Oily excipients or solvents which can be used are, in particular, vegetable and animal oils, such as, for example, sunflower oil or codliver oil.
• the daily dose can be about 50 mg to 5 g.
• One dosage unit preferably contains 250 to 500 mg.
• the formulations can also contain, in addition to the conventional fillers and excipients, an antihypertensive agent, such as, for example, a saluretic agent, reserpine, hydralazine, guanethidine, ⁇ -methyl-dopa, clonidine or a ⁇ -sympathicolytic agent, or an agent having an antihyperuricaemic action, an oral antidiabetic agent, an agent for the treatment of geriatric symptoms or an agent which improves the circulation.
• an antihypertensive agent such as, for example, a saluretic agent, reserpine, hydralazine, guanethidine, ⁇ -methyl-dopa, clonidine or a ⁇ -sympathicolytic agent, or an agent having an antihyperuricaemic action, an oral antidiabetic agent, an agent for the treatment of geriatric symptoms or an agent which improves the circulation.
• the pure precursors, according to the invention, of the general formula IV have a distinctly weaker effect on the serum lipoproteins--if they have any effect at all--but, like structurally related thiazolidine derivatives (compare German Offenlegungsschrift 2,436,263), they possess a salidiuretic activity, which is very good in some cases.
• Example 1 Obtained analogously to Example 1 (a) from 2,4'-dichloro-3'-dimethylsulfamoyl-acetophenone and 1-methyl-3-phenylthiourea. Colorless crystals; melting point 228° C. (with decomposition).
• Example 3 (c) Obtained by a procedure analogous to that indicated in Example 3 (c), from 4-(4-chloro-3-dimethylsulfamoylphenyl)-3-methyl-2-phenylimino-4-thiazoline and 0.02 mole of methanesulfonic acid. Colorless crystals; melting point 198°-199° C.
• Example 1 Obtained by a procedure analogous to that indicated in Example 1 (b), from 4-(4-chloro-3-dimethylsulfamoylphenyl)-3-methyl-2-(2-methylphenylimino)thiazolidin-4-ol hydrobromide, and the crystals which precipitate as a sparingly double compound from glacial acetic acid are filtered off at room temperature. Colorless crystals; melting point 256° C.
• Example 2 (a) Obtained by a procedure analogous to that indicated in Example 2 (a), from 4-(4-chloro-3-dimethylsulfamoylphenyl)-3-methyl-2-(2-methylphenylimino)-4-thiazoline hydrobromide with triethylamine in methanol. Colorless crystals from methanol/ethyl acetate; melting point 158°-162° C.
• Example 2 (a) Obtained by a procedure analogous to that indicated in Example 2 (a), from 4-(4-chloro-3-dimethylsulfamoylphenyl)-2-(4-fluorophenyl-imino)-3-methyl-4-thiazoline hydrobromide. Colorless to pale yellow crystals; melting point 144°-145° C.
• Example 2 Obtained by a procedure analogous to that indicated in Example 1 (b), from 2-(4-diethylaminophenyl-imino)-4-(4-chloro-3-dimethylsulfamoylphenyl)-3-methyl-thiazolidin-4-ol hydrobromide. After heating in glacial acetic acid, the solvent is distilled off until the volume is 30 ml, and the desired product is precipitated with 150 ml of diisopropyl ether. Colorless crystals; melting point 257° C. (with decomposition).
• Example 2 (a) Obtained by a procedure analogous to that indicated in Example 2 (a), from 2-(4-diethylaminophenyl-imino)-4-(4-chloro-3-dimethylsulfamoylphenyl)-3-methyl-4-thiazoline hydrobromide and triethylamine in methanol at room temperature. Melting point 184°-185° C.
• Example 2 Obtained by a procedure analogous to that indicated in Example 1 (b), from 4-(4-chloro-3-dimethylsulfamoylphenyl)-2-(4-methoxyphenyl-imino)-3-methylthiazolidin-4-ol hydrobromide. After distilling off the glacial acetic acid, the residue is several times boiled with acetone and the crystals are filtered off. Melting point 240°-241° C. (with decomposition).
• Example 14 Obtained by a procedure analogous to that indicated in Example 2 (a), from the hydrobromide of the title compound (Example 14) and triethylamine in ethanol. Colorless crystals; melting point 198°-199° C.
• Example 2 (a) Obtained by a procedure analogous to that indicated in Example 2 (a), from the hydrobromide of the title compound of Example 16 and triethylamine. Melting point 147°-151° C.
• Example 2 (a) Obtained by a procedure analogous to that indicated in Example 2 (a), from 4-(4-chloro-3-dimethylsulfamoylphenyl)-3-methyl-2-(2,4-dimethylphenyl-imino)-4-thiazoline hydrobromide. Colorless crystals; melting point 152°-154° C.
• Example 2 (a) Obtained by a procedure analogous to that indicated in Example 2 (a), from 2-(4-chloro-3-methylphenyl-imino)-4-(4-chloro-3-dimethylsulfamoylphenyl)-3-methyl-4-thiazoline hydrobromide and triethylamine. Melting point 137°-141° C.
• Example 22 Obtained by a procedure analogous to that indicated in Example 2 (a), from the hydrobromide of the title compound (Example 22) and triethylamine. Colorless crystals; melting point 184° C.
• Example 1 Obtained by a procedure analogous to that indicated in Example 1 (b), from 4-(4-chloro-3-dimethylsulfamoylphenyl)-3-methyl-2-(2,3-dimethylphenyl-imino)thiazolidin-4-ol hydrobromide, by boiling in glacial acetic acid for 2 hours and filtering off the crystals at room temperature. Colorless crystals from glacial acetic acid; melting point 256° C. (with decomposition).
• Example 2 (a) Obtained by a procedure analogous to that indicated in Example 2 (a), from 4-(4-chloro-3-dimethylsulfamoylphenyl)-3-methyl-2-(2,3-dimethylphenyl-imino)-4-thiazoline hydrobromide and triethylamine in methanol. Melting point 226° C.
• Example 2 Obtained by a procedure analogous to that indicated in Example 1 (b), from 2-(3-chloro-2-methylphenyl-imino)-4-(4-chloro-3-dimethylsulfamoylphenyl)-3-methylthiazolidin-4-ol hydrobromide, by heating under reflux for 20 minutes in glacial acetic acid or by heating at 110° C. in propionic acid for 45 minutes. Colorless crystals; melting point 226°-228° C. (with decomposition).
• Example 2 (a) Obtained by a procedure analogous to that indicated in Example 2 (a), from 2-(3-chloro-2-methylphenyl-imino)-4-(4-chloro-3-dimethylsulfamoylphenyl)-3-methyl-4-thiazoline hydrobromide, the reaction mixture being rendered alkaline with a 20% methanolic ammonia solution instead of with triethylamine and worked up as in Example 2 (a). Colorless crystals; melting point 144°-146° C.
• Example 2 Obtained by a procedure analogous to that indicated in Example 1 (b), from 2-(4-chloro-2-methoxyphenyl-imino)-4-(4-chloro-3-dimethylsulfamoylphenyl)-3-methylthiazolidin-4-ol hydrobromide, by boiling for 30 minutes in formic acid, then distilling off the solvent, treating the residue with ethyl acetate or diisopropyl ether and filtering off the solid. Melting point 244° C. (with decomposition).
• Example 1(a) Obtained by a procedure analogous to that indicated in Example 1(a), from 2-bromo-4'-chloro-3'-dimethylsulfamoylacetophenone and 3-sec.-butyl-1-phenylthiourea, or by a procedure analogous to that of Example 1(b), from 3-sec.-butyl-4-(4-chloro-3-dimethylsulfamoylphenyl)-2-phenyliminothiazolidin-4-ol hydrobromide. Colorless crystals; melting point 250° C. (with decomposition).
• Example 1(a) Obtained (a) by a procedure analogous to that indicated in Example 1(a), from 2-bromo-4'-chloro-3'-dimethylsulfamoylacetophenone and 3-n-hexyl-1-phenylthiourea, or (b) by a procedure analogous to that indicated in Example 1(b), from 4-(4-chloro-3-dimethylsulfamoylphenyl)-3-n-hexyl-2-phenyliminothiazolidin-4-ol hydrobromide. Colorless crystals; melting point 234° C. (with decomposition).
• Example 1(a) Obtained (a) by a procedure analogous to that indicated in Example 1(a), from 3'-diethylsulfamoyl-2-bromo-4'-chloroacetophenone and 1-(4-chlorophenyl)-3-methylthiourea, or (b) by a procedure analogous to that of Example 1(b), by boiling 4-(3-diethylsulfamoyl-4-chlorophenyl)-2-(4-chlorophenyl-imino)-3-methylthiazolidin-4-ol hydrobromide for 2 hours in glacial acetic acid and filtering off the crystals after cooling. Melting point 207° C. (with decomposition).
• Example 51 Obtained by a procedure analogous to that indicated in Example 2(a), from the corresponding hydrobromide (Example 51). Colorless crystals; melting point 198° C.
• Example 51(b) Obtained by a procedure analogous to that indicated in Example 51(b), from 4-(3-diethylsulfamoyl-4-chlorophenyl)-3-methyl-2-(2-methylphenyl-imino)-thiazolidin-4-ol hydrobromide. Colorless crystals; melting point 258° (with decomposition).
• Example 53 Obtained by a procedure analogous to that indicated in Example 2(a), from the corresponding hydrobromide (Example 53). Colorless crystals; melting point 166° C.
• Example 57 Obtained by a procedure analogous to that indicated in Example 2(a), from the corresponding hydrobromide (Example 57) and triethylamine. Colorless crystals; melting point 114°-116° C.
• Example 51(b) Obtained by a procedure analogous to that indicated in Example 51(b), from 4-(4-chloro-3-dipropylsulfamoylphenyl)-3-methyl-2-(2,4-dimethylphenyl)thiazolidin-4-ol hydrobromide. Colorless crystals; melting point 239°-241° C. (with decomposition).
• Example 59 Obtained by a procedure analogous to that indicated in Example 2(a), from the corresponding hydrobromide (Example 59). Colorless crystals; melting point 139°-141° C.
• Example 1(b) Obtained by a procedure analogous to that indicated in Example 1(b), from 4-(4-chloro-3-dipropylsulfamoylphenyl)-3-methyl-2-(2,3-dimethylphenyl-imino)thiazolidin-4-ol hydrobromide by refluxing in glacial acetic acid, subsequently evaporating and crystallizing the viscous residue under water. Colorless crystals from methanol/ether; melting point 210°-212°.
• Example 61 Obtained by a procedure analogous to that indicated in Example 2(a), from the hydrobromide of the title compound (Example 61). Colorless crystals; melting point 184°-187° C.
• Example 2(b) Obtained by a procedure analogous to that indicated in Example 2(b), from 4-(4-chloro-3-N-morpholinosulfonylphenyl)-3-methyl-2-phenyliminothiazolidin-4-ol by boiling in glacial acetic acid and precipitating with diisopropyl ether. Melting point 212°-214° C.
• Example 2(b) Obtained by a procedure analogous to that indicated in Example 2(b), from 4-[4-chloro-3-(1-methyl-4-piperazinylsulfonyl)-phenyl]-3-methyl-2-phenyliminothiazolidin-4-ol, by boiling with glacial acetic acid and subsequently distilling off the solvent. Water is added to the residue and the pH is adjusted to 13 with 2 N NaOH. The crystals are filtered off and recrystallized from isopropanol. Melting point 156°-158° C.
• Example 2(b) Obtained by a procedure analogous to that indicated in Example 2(b), from 4-[4-chloro-3-(3,5-dimethylmorpholino-N-sulfonyl)-phenyl]-3-methyl-2-phenylimino-4-thiazoline. Colorless crystals; melting point 190°-192° (from ethanol).
• the reaction mixture After adding catalytic amounts of benzyl-triethyl-ammonium chloride as a phase transfer catalyst and 0.024 mole of dimethyl sulfate, the reaction mixture is heated to 80° to 90° C., with stirring and maintaining the pH value, and dimethyl sulfate is added in approximately 1 g portions at approximately 2 hour intervals until the thin layer chromatogram on silica gel (1:1 toluene/ethyl acetate) indicates complete conversion.
• the organic phase is stirred with aqueous ammonia solution for 4 hours at 40°, in order to decompose any amounts of dimethyl sulfate which may be present, and dried over sodium sulfate and the solvent is distilled off. Colorless crystals, melting point 179°-180° C. (from glacial acetic acid).
• a suspension of 2.05 g of N-methyl-N'-phenylchloroformamidine hydrochloride in 8 ml of chloroform is added, at 10°-12° C., to 6 g of 20% strength sodium hydroxide solution.
• the mixture is stirred for 10 minutes, the organic phase is separated off, the aqueous phase is extracted twice more with chloroform and the combined organic phases are dried over K 2 CO 3 . After filtering off the desiccant, the solution is subjected to further reaction without isolating the carbodiimide.
• a solution of 2 g of triethylamine in 10 ml of isopropanol is added dropwise in the course of 30 minutes to a mixture of 3 g of 4'-chloro-3'-dimethylsulfamoylacetophenone-2-thiol and 2.1 g of N-methyl-N'-phenylchloroformamidine hydrochloride in 50 ml of isopropanol, with the exclusion of moisture and with external cooling, the reaction temperature being kept between 10° and 15° C. during the addition.
• reaction mixture is poured into 300 ml of water and the resulting mixture is saturated with sodium chloride and extracted several times with ethyl acetate. After the combined organic phases have been washed with water and dried over sodium sulfate, they are concentrated in a rotary evaporator. Colorless crystals with a melting point of 145° C. (with decomposition).
• the 2'-chloro-5'-dimethylsulfamoylacetophenone-2-thiol used is obtained in the form of a pale yellow crystalline powder by alkaline hydrolysis of 2-acetylthio-2'-chloro-5'-dimethylsulfamoylacetophenone with 5% strength aqueous sodium hydroxide solution at room temperature, under an argon atmosphere as the blanketing gas.
• 2-Acetylthio-2'-chloro-5'-dimethylsulfamoylacetophenone is obtained by reacting 2-bromo-2'-chloro-5'-dimethylsulfamoylacetophenone with thioacetic acid, which has been neutralized with KOH, in ethanol. After the reaction, the reaction mixture is poured into water, the resulting mixture is extracted with ethyl acetate, the organic phase is dried over magnesium sulfate and the residue obtained by evaporation of the solvent is recrystallized from isopropanol (active charcoal). Melting point 84°-88° C.
• bromoacetophenones listed below were prepared in an analogous manner: 2,2'-dibromo-5'-dimethylsulfamoyl-acetophenone, melting point 88° C., 2-bromo-3'-chloro-5'-dimethylsulfamoyl-acetophenone, melting point 77°-78° C., 2-bromo-2'-chloro-5'-methylsulfamoyl-acetophenone, melting point 99°-101° C., 2-bromo-2'-chloro-5'-dimethylsulfamoyl-acetophenone, melting point 87°-88° C., 2-bromo-2'-chloro-5'-sulfamoylacetophenone, melting point 152°-154° C., 2-bromo-3'-methyl-5'-dimethylsulfamoylacetophenone, melting point 71°-75° C., 2-bromo-2'-methyl-5'-d
• 0.25 ml of carbon tetrachloride is added to a suspension of 2.7 g (0.11 mole) of magnesium turnings in 2.5 g (0.043 mole) of anhydrous alcohol, the temperature rising to 40° C., and 75 ml of ethanol (absolute) are then added slowly dropwise.
• the mixture is heated to the boil and a small portion of a solution of 17.6 g (0.11 mole) of diethyl malonate, 10 ml (0.17 mole) of absolute ethanol and 12.5 ml of diethyl ether is added. After the reaction has started, the remainder of the solution is added dropwise at a rate such that the mixture remains at the boil without external heating.
• the mixture is then heated for a further 3 hours under reflux, during which time the magnesium is dissolved, and a solution of 11.6 g (0.05 mole) of 2-methyl-5-sulfamoylbenzoyl chloride in 100 ml of ethyl acetate is added dropwise, whilst keeping the mixture at the boil, and the resulting mixture is boiled for a further 2 hours under a reflux condenser.
• the reaction mixture is poured into a mixture of 15 g of concentrated sulfuric acid, 200 ml of water and 300 ml of ethyl acetate and extracted, the organic phase is separated off and the aqueous phase is twice more extracted by shaking with ethyl acetate.
• the product phase is dried over magnesium sulfate, the solvent is distilled off and the oily residue (diethyl 2'-methyl-5'-sulfamoylbenzoyl-malonate) is further processed without any further purification operation.
• the 2'-methyl-5'-sulfamoylbenzoyl-malonate obtained as an oil is slowly warmed to 110° C. and the dropwise addition of 18 ml of 85% strength phosphoric acid is started when the temperature reaches about 80° C.
• the reaction mixture is warmed until the evolution of CO 2 has ceased and is then heated at 110° C. for a further half hour.
• about 200 ml of water are added, the resulting mixture is extracted several times with ethyl acetate, the combined organic phases are washed with water and dried over MgSO 4 , the solvent is driven off, diisopropyl ether is added to the residue and the crystals are filtered off. Crystals with a melting point of 115°-117° C.
• the sulfamoylacetophenone derivatives listed below are prepared in an analogous manner: 2'-methyl-5'-dimethylsulfamoyl-acetophenone, melting point 54°-56° C., 3'-methyl-5'-sulfamoyl-acetophenone, melting point 165°-168° C., 3'-methyl-5'-dimethylsulfamoyl-acetophenone, melting point 106°-109° C., 2'-chloro-5'-sulfamoyl-acetophenone, melting point 114°-116° C., 2'-chloro-5'-dimethylsulfamoyl-acetophenone, melting point 79° C., 2'-chloro-5'-methylsulfamoyl-acetophenone, melting point 74°-75° C., 3'-chloro-5'-dimethylsulfamoyl-acetophenone, melting point 100°-102°
• the corresponding chlorosulfonylbenzoic acids are obtained in a manner which is in itself known, by heating the benzoic acids with chlorosulfonic acids at 120° to 165° C. and then decomposing the reaction mixture, after cooling, by adding dropwise to an ice/water mixture: 2-methyl-5-chlorosulfonylbenzoic acid, melting point 151°-155° C., 3-methyl-5-chlorosulfonylbenzoic acid, melting point 176°-180° C., 3-chloro-5-chlorosulfonylbenzoic acid and 2-bromo-5-chlorosulfonylbenzoic acid.

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